Grb2 associated binder 2 couples B-cell receptor to cell survival.
B-cell fate during maturation and the germinal center reaction is regulated through the strength and the duration of the B-cell receptor signal. Signaling pathways discriminating between apoptosis and survival in B cells are keys in understanding adaptive immunity. Gab2 is a member of the Gab/Dos adaptor protein family. It has been shown in several model systems that Gab/Dos family members may regulate both the anti-apoptotic PI3-K/Akt and the mitogenic Ras/MAPK pathways, still their role in B-cells have not been investigated in detail. Here we studied the role of Gab2 in B-cell receptor mediated signaling. We have shown that BCR crosslinking induces the marked phosphorylation of Gab2 through both Lyn and Syk kinases. Subsequently Gab2 recruits p85 regulatory subunit of PI3-K, and SHP-2. Our results revealed that Ig-alpha/Ig-beta, signal transducing unit of the B-cell receptor, may function as scaffold recruiting Gab2 to the signalosome. Overexpression of Gab2 in A20 cells demonstrated that Gab2 is a regulator of the PI3-K/Akt but not that of the Ras/MAPK pathway in B cells. Accordingly to the elevated Akt phosphorylation, overexpression of wild-type Gab2 in A20 cells suppressed Fas-mediated apoptosis, and enhanced BCR-mediated rescue from Fas-induced cell death. Although PH-domain has only a stabilizing effect on membrane recruitment of Gab2, it is indispensable in mediating its anti-apoptotic effect.
Maus
Máté
M
Department of Immunology at Eötvös Loránd University, Pázmány Péter sétány. 1/c, Budapest, 1117, Hungary.
Medgyesi
Dávid
D
Kövesdi
Dorottya
D
Csuka
Dorottya
D
Koncz
Gábor
G
Sármay
Gabriella
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D001665:Binding Sites; D002470:Cell Survival; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000888:Antibodies, Anti-Idiotypic; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D019014:fas Receptor; D019061:src-Family Kinases; C490894:Gab2 protein, mouse; C048844:anti-IgG; C044203:anti-IgM